Mutations in HPCA cause autosomal-recessive primary isolated dystonia

Am J Hum Genet. 2015 Apr 2;96(4):657-65. doi: 10.1016/j.ajhg.2015.02.007. Epub 2015 Mar 19.


Reports of primary isolated dystonia inherited in an autosomal-recessive (AR) manner, often lumped together as "DYT2 dystonia," have appeared in the scientific literature for several decades, but no genetic cause has been identified to date. Using a combination of homozygosity mapping and whole-exome sequencing in a consanguineous kindred affected by AR isolated dystonia, we identified homozygous mutations in HPCA, a gene encoding a neuronal calcium sensor protein found almost exclusively in the brain and at particularly high levels in the striatum, as the cause of disease in this family. Subsequently, compound-heterozygous mutations in HPCA were also identified in a second independent kindred affected by AR isolated dystonia. Functional studies suggest that hippocalcin might play a role in regulating voltage-dependent calcium channels. The identification of mutations in HPCA as a cause of AR primary isolated dystonia paves the way for further studies to assess whether "DYT2 dystonia" is a genetically homogeneous condition or not.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / metabolism
  • Calcium Channels / metabolism
  • Dystonia / genetics*
  • Genes, Recessive / genetics*
  • Hippocalcin / genetics*
  • Hippocalcin / metabolism
  • Homozygote
  • Humans
  • Mutation / genetics*
  • Pedigree


  • Calcium Channels
  • HPCA protein, human
  • Hippocalcin